14 research outputs found

    Elevated levels of tumor apolipoprotein D independently predict poor outcome in breast cancer patients

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    First published:28 January 2020Aims: Apolipoprotein D (ApoD) is an androgen and estrogen regulated protein and a major constituent of breast cysts. Although reported to be a marker of breast cancer, the prognostic importance of ApoD in invasive breast cancer is unclear. AIM:To investigate the relationship between ApoD protein expression, together with estrogen receptor alpha (ERα) or androgen receptor (AR) expression, in predicting breast cancer outcome. Methods and results: ApoD levels were measured using immunohistochemistry and video image analysis (VIA) on tissue sections from a breast cancer cohort (n=214). We assessed the association of ApoD with disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS). We further assessed the relationship between ApoD, AR and ERα in predicting OS. RESULTS:ApoD expression (>1% ApoD positivity) was detected in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, 4th quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with ERα positive cancers with low (<20.7%) ApoD positivity, or those containing high (≥78%) AR and low (<20.7%) ApoD positivity had a better OS than other patient groups. Conclusions: ApoD expression could be used to predict breast cancer prognosis independent of ERα and AR.Tanja Jankovic‐Karasoulos, Tina Bianco‐Miotto, Miriam S Butler, Lisa M Butler, Catriona M McNeil, Sandra A O’Toole ... et al

    Suppression of Integrin Activation by Activated Ras or Raf Does Not Correlate with Bulk Activation of ERK MAP Kinase

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    The rapid modulation of ligand-binding affinity (“activation”) is a central property of the integrin family of cell adhesion receptors. The Ras family of small GTP-binding proteins and their downstream effectors are key players in regulating integrin activation. H-Ras can suppress integrin activation in fibroblasts via its downstream effector kinase, Raf-1. In contrast, to H-Ras, a closely related small GTP-binding protein R-Ras has the opposite activity, and promotes integrin activation. To gain insight into the regulation of integrin activation by Ras GTPases, we created a series of H-Ras/R-Ras chimeras. We found that a 35-amino acid stretch of H-Ras was required for full suppressive activity. Furthermore, the suppressive chimeras were weak activators of the ERK1/2 MAP kinase pathway, suggesting that the suppression of integrin activation may be independent of the activation of the bulk of ERK MAP kinase. Additional data demonstrating that the ability of H-Ras or Raf-1 to suppress integrin activation was unaffected by inhibition of bulk ERK1/2 MAP kinase activation supported this hypothesis. Thus, the suppression of integrin activation is a Raf kinase induced regulatory event that can be mediated independently of bulk activation of the ERK MAP-kinase pathway

    Disruption of C-Terminal Cytoplasmic Domain of βPS Integrin Subunit Has Dominant Negative Properties in Developing Drosophila

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    We have analyzed a set of new and existing strong mutations in the myospheroid gene, which encodes the βPS integrin subunit of Drosophila. In addition to missense and other null mutations, three mutants behave as antimorphic alleles, indicative of dominant negative properties. Unlike null alleles, the three antimorphic mutants are synthetically lethal in double heterozygotes with an inflated (αPS2) null allele, and they fail to complement very weak, otherwise viable alleles of myospheroid. Two of the antimorphs result from identical splice site lesions, which create a frameshift in the C-terminal half of the cytoplasmic domain of βPS. The third antimorphic mutation is caused by a stop codon just before the cytoplasmic splice site. These mutant βPS proteins can support cell spreading in culture, especially under conditions that appear to promote integrin activation. Analyses of developing animals indicate that the dominant negative properties are not a result of inefficient surface expression, or simple competition between functional and nonfunctional proteins. These data indicate that mutations disrupting the C-terminal cytoplasmic domain of integrin β subunits can have dominant negative effects in situ, at normal levels of expression, and that this property does not necessarily depend on a specific new protein sequence or structure. The results are discussed with respect to similar vertebrate β subunit cytoplasmic mutations
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